In recent years it has become apparent that the human chondrodystrophies represent a genetically heterogeneous group of disorders. The extent of this heterogeneity, however, has not yet been fully recognized, and little is known about the pathogenesis of most of these disorders. The objectives of this research project will be to: 1) delineate the variability and true heterogeneity of the chondrodystrophies; 2) to define the mechanism by which each is inherited; 3) to characterize the specific histological, ultrastructural and biochemical pathogenetic mechanisms which lie between each specific mutant gene and the resultant phenotype. All patients and selected members of their families will undergo full clinical, radiographic and metabolic examinations. Selected patients will then be subjected to a biopsy of the costochondral junction and iliac crest. The cartilagenous tissue obtained will be studied by 1) histological, 2) histochemical, 3) ultrastructural, 4) biochemical and metabolic procedures. In vitro cultures of differentiated chondrocytes will be established from these biopsies; collagen and mucopolysaccharide synthesis, secretion and degradation will be studied by radioisotope and chromatographic techniques. Similar studies will be performed on cartilagenous tissue obtained from age matched controls undergoing elective chest surgery. A number of animal models with genetic chondrodystrophies will be studied in a similar manner.